Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure.

Abstract

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

• Authors: Andrea Ruiz-Velasco, Min Zi, Susanne S Hille, Tayyiba Azam, Namrita Kaur, Juwei Jiang, Binh Nguyen, Karolina Sekeres, Pablo Binder, Lucy Collins, Fay Pu, Han Xiao, Kaomei Guan, Norbert Frey, Elizabeth J Cartwright, Oliver J Müller, Xin Wang, Wei Liu
• Journal: eLife (Elife) Vol. 9 (03 30 2020) ISSN: 2050-084X [Electronic] England
• PMID: 32223896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020, Ruiz-Velasco et al.

Chemical References

• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• MIRN128 microRNA, human
• MicroRNAs
• Mirn128 microRNA, mouse
• MAPK7 protein, human
• Mitogen-Activated Protein Kinase 7

Topics

• Animals
• Apoptosis
• Heart Failure (prevention & control)
• Humans
• Insulin Receptor Substrate Proteins (genetics)
• Insulin Resistance
• Male
• Mice, Inbred C57BL
• MicroRNAs (genetics)
• Mitogen-Activated Protein Kinase 7 (genetics, metabolism)
• Myocardial Ischemia (genetics, prevention & control)
• Myocytes, Cardiac (pathology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction